The present invention relates to new dihydropyridine derivatives, and the use of the dihydropyridine derivatives as medicines. It is said that the activation of N-type calcium channel is concerned with diseases such as encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e. g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury; various pains, e. g. sharp pain caused by spinal injury, diabetes or thromboangitis obliterans; pain after an operation; migraine and visceral pain; various diseases caused by psychogenic stress, e. g. bronchial asthma; unstable angina and hypersensitive colon inflammation; emotional disorder; and drug addiction withdrawal symptoms, e. g. ethanol addiction withdrawal symptoms. The compounds of the present invention are effective in inhibiting the activation of N-type calcium channel and, therefore, they are usable as remedies for the above-described diseases.
The calcium channels are now classified into subtypes L, N, P, Q, R and T. Each of the subtypes is distributed specifically to organs. Particularly, it is known that N-type calcium channel is widely distributed in the central nerves, peripheral nerves and adrenal medulla cells and that this calcium channel is concerned with the death of neurons, control of blood catecholamine dynamics and control of senses such as perceptivity.
It was confirmed that peptides, omega conotoxin GVIA and omega conotoxin MVIIA which selectively inhibit the function of N-type calcium channel inhibit the release of excitatory neurotransmitter from a brain slice sample. It was confirmed by animal experiments that they prevent the advancement of neuron necrosis in a cerebrovascular disorder. It is generally considered that a compound having a clinical effect of inhibiting the function of N-type calcium channel is effective in curing encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e. g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury. In addition, it was also confirmed by animal experiments that omega conotoxin MVIIA gets rid of formalin-caused sharp pain, hot plate pain, sharp pain caused by peripheral neuropathy, etc. Therefore, this medicine is considered to be clinically effective for relieving various pains such as sharp pain caused by spinal injury, diabetes or thromboangitis obliterans; pain after an operation; migraine; and visceral pain. Further, omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, the constriction reaction of an isolated blood vessel by the electric stimulation of governing nerves, and the acceleration of catecholamine secretion from dog adrenal medulla, etc. Therefore, it is considered that compounds having the N-type calcium channel-inhibiting activity are clinically effective in treating various diseases caused by psychogenic stress, e. g. bronchial asthma, unstable angina and hypersensitive colon inflammation [Neuropharmacol., 32, 1141 (1993)].
Although several peptide compounds and non-peptide compounds which selectively react on the N-type calcium channel have been disclosed hitherto (for example, WO 9313128), they are not yet used as practical medicines. Some of known compounds which react on the N-type calcium channel also react on other calcium channels than the N-type calcium channel [British Journal of Pharmacology, 122 (1), 37-42, 1997]. For example, compounds which are also antagonistic to L-type calcium channel, which deeply concern with the hypotensive effect, were incompatible with diseases for which N-type antagonists are efficacious (such as cerebral stroke, and pain caused of neuralgia, terminal cancer, spinal injury or the like).
An object of the present invention is to provide new compounds having a selectively antagonistic effect on N-type calcium channel.
Another object of the present invention is to provide antagonists to the N-type calcium channel.
Still another object of the present invention is to provide remedies for encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction or cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after an operation, migraine, visceral pain, bronchial asthma, unstable angina, hypersensitive colon inflammation and drug addiction withdrawal symptoms.
A further object of the present invention is to provide a medicinal composition.
The above-described objects and other objects of the present invention will be apparent from the following description and Examples.
The inventors synthesized various dihydropyridine derivatives, and made investigations on the effects of these newly synthesized compounds and known dihydropyridine derivatives for inhibiting the electric current of N-type calcium channel. After the investigations, the inventors have found that some specified, new dihydropyridine derivatives have excellent, selective antagonistic effect on the N-type calcium channel. The present invention has been completed on the basis of this finding.
Namely, the present invention provides dihydropyridine derivatives of following general formula (1) or pharmaceutically acceptable salts thereof: 
wherein
A represents a group of following general formula (2), 1-naphthyl group, 2-naphthyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, indole-2-yl group or indole-3-yl group: 
wherein R1, R2, R3 R4 and R5 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl group, a heteroaryl group, an aryl-lower alkoxyl group or an aroyl group,
B represents cyano group, nitro group, acetyl group, tetrazole group, triazole group or a group of following general formula (3) or (4): 
xe2x80x83wherein
R6 to R8 each represent hydrogen atom, a linear or branched, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, an alkyl group substituted with a cyclic alkyl group (which may contain a hetero atom), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a heteroaryl-lower alkyl group (excluding pyridine-3-ylpropyl group), a heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a cyano-lower alkenyl group, and the chains in R6 to R8 may have a hetero atom, and
R7 and R8 may together form a ring which may contain a hetero atom,
C represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group or a halogeno-lower alkyl group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group or a halogeno-lower alkyl group,
F represents an aryl group, a heteroaryl group or a cyclic alkyl group (which may have a hetero atom),
G represents hydrogen atom or a lower alkyl group,
X1 represents an interatomic bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and
Y represents a group of any of following general formulae (5) to (14): 
wherein two of R9 to R12 and R0 may be the same or different from each other, and each represent hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a thio-lower alkyl group, an alkylthio-lower alkyl group, an aryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group, B and C may together form a lactone ring or lactam ring or two of R1 to R3 may be bonded together to form a ring, and R9 and R10 may be bonded together to form a ring.
The present invention also provides an antagonist to the N-type calcium channel, which contains a dihydropyridine derivative of above general formula (1) or general formula (1-1) given below or a pharmaceutically acceptable salt thereof as the active ingredient.
The present invention further provides a medicine containing the above-described dihydropyridine derivative or a pharmaceutically acceptable salt thereof as the active ingredient, and usable for any of encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after an operation, migraine and visceral pain, bronchial asthma, unstable angina, hypersensitive colon inflammation, and drug addiction withdrawal symptoms. 
wherein A represents a group of following general formula (2), 1-naphthyl group, 2-naphthyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, indole-2-yl group, indole-3-yl group, quinoline-2-yl group, quinoline-3-yl group, quinoline-4-yl group, quinoline-5-yl group, quinoline-6-yl group, quinoline-7-yl group, quinoline-8-yl group, another heteroaryl group, cyclohexyl group, cyclopentyl group or a cyclic alkyl group (which may contain a hetero group),
B is as defined above in general formula (1),
C represents hydrogen atom, dimethoxymethyl group, cyano group, a lower alkyl group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group,
D is as defined above in general formula (1),
E represents hydrogen atom, dimethoxymethyl group, cyano group, a lower alkyl group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group,
X1 is as defined above in general formula (1),
J represents a group of following formulae (J-1) to (J-3): 
wherein F in formula (J-1) represents an aryl group, a heteroaryl group or a cyclic alkyl group (which may contain a hetero atom),
F and G are as defined in general formula (1),
Y is as defined in general formula (1), or represents a group of following formula (22) or (23): 
wherein m in formulae (J-2) and (J-3) represents an integer of 1 to 3, n represents an integer of 2 or 3, I represents an aryl group, a heteroaryl group, a cyclic alkyl group (which may contain a hetero atom) or a group of following formula (Ia): 
wherein k is 0, 1 or 2, P and Q may be the same or different from each other, and each represent hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a thio-lower alkyl group, an alkylthio-lower alkyl group, an aryl group, an aryl-lower alkyl group, a heteroaryl group or a heteroaryl-lower alkyl group, or P and Q together form a ring which may contain a hetero atom,
B and C may together form a lactone ring or lactam ring or two of R1 to R3 may be bonded to form a ring, and R9 and R10 may be bonded together to form a ring.
The present invention also provides a medicinal composition containing the above-described dihydropyridine derivative of general formula (1) or a pharmaceutically acceptable salt thereof, a carrier and/or a diluent.
The term xe2x80x9clowerxe2x80x9d in, for example, lower alkyl groups, herein indicates that the groups have 1 to 6 carbon atoms. The alkyl groups themselves and the alkyl groups in the alkoxyl, alkenyl, alkylamino, alkylthio and alkanoyl groups may be either linear or branched. The alkyl groups are, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group and secondary and tertiary butyl groups. Among them, those having 1 to 3 carbon atoms are preferred. The aryl-lower alkoxyl groups include, for example, benzyloxy group. The halogen atoms indicate fluorine, chlorine, bromine and iodine atoms. Examples of the aryl groups herein include substituted and unsubstituted aryl groups, preferably substituted or unsubstituted phenyl groups, and the substituents thereof are particularly preferably halogens, alkyl groups and alkoxyl groups. The heteroaryl groups are substituted or unsubstituted heteroaryl groups, such as preferably, pyridyl group, furyl group, and substituted pyridyl and furyl groups. Particularly preferred examples of the substituents are halogens, alkyl groups and alkoxyl groups. Examples of the aroyl groups include benzoyl group and pyridylcarbonyl group.
The substituents of the substituted aryl groups or substituted heteroaryl groups in R6 to R8 in the groups represented by general formula (3) or (4) are, for example, halogen atoms (such as fluorine, chlorine, bromine and iodine), hydroxyl group, carboxyl group, cyano group, nitro group, lower alkyl groups, lower alkoxyl groups, halogeno-lower alkyl groups and lower alkoxycarbonyl groups.
1-Naphthyl group, 2-naphthyl group, indole-2-yl group and indole-3-yl groups represented by A in general formula (1) are either unsubstituted or substituted, and the substituents of them are the same as those described above with reference to R6 to R8.
Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group and pyridine-2-yl group represented by A are also unsubstituted or substituted. When they have two or more substituents, the substituents may form a ring together. The substituents are those described above with reference to 1-naphthyl group. The rings formed by those substituents include benzothiophene, benzofuran, quinoline, isoquinoline, etc.
Quinoline-2-yl group, quinoline-3-yl group, quinoline-4-yl group, quinoline-5-yl group, quinoline-6-yl group, quinoline-7-yl group and quinoline-8-yl group represented by A in general formula (1-1) are either unsubstituted or substituted, and the substituents of them are the same as those described above with reference to 1-naphthyl group or the like. Heteroaryl groups, cyclohexyl group, cyclopentyl group and other cyclic alkyl groups are also unsubstituted or substituted. When they have two or more substituents, these substituents may form a ring together. The substituents are those described above with reference to 1-naphthyl group. The rings formed by these substituents include acridine, benzothiazole, benzoxazole, tetrahydronaphthalene, indan, etc.
The heteroaryl groups and other cyclic alkyl groups include, for example, thiazole, oxazole, pyrimidine, pyrazine and pyridazine; and cyclopropyl, cyclobutyl, cycloheptyl and cyclooctyl groups.
The groups other than those described above as groups represented by A in above general formula (1-1) are the same as those represented with reference to groups represented by A in general formula (1).
The lower alkyl groups, hydroxy-lower alkyl groups, halogeno-lower alkyl groups, amino-lower alkyl groups, azido-lower alkyl groups, aryl-lower alkyl groups and heteroaryl-lower alkyl groups may contain a hetero atom in their chains. The hetero atoms include oxygen, nitrogen and sulfur atoms, and the chains containing the hetero atoms are, for example, hydroxyethoxymethyl group, methoxyethyl group, aminoethoxymethyl group, azidoethoxymethyl group and methylthioethyl group.
F in general formula (1) is preferably a group of following formula (15), thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, cyclohexyl group, pyrrolidine-1-yl group, morpholine-4-yl group, imidazole-1-yl group or pyrrolidinone-1-yl group: 
wherein
R13, R14, R15 R16 and R17 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group, carbamoyl which may have a substituent, a carboxyamide group which may have a substituent, an aroyl group, an aryl group, a heteroaryl group or a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, which may have a hetero atom in its chain if necessary; and
two of R13 to R15 may be bonded together to form a ring.
Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, cyclohexyl group and pyrrolidine-1-yl group may be either unsubstituted or substituted. When they have two or more substituents, they may form a ring together. The substituents are those described above with reference to R6 to R8. The rings formed by those substituents are, for example, those described above with reference to group A.
F in general formula (1-1) is preferably a group of above formula (15), thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, imidazole-1-yl group, another heteroaryl group, piperidine-1-yl group, piperidine-4-yl group, pyrrolidine-1-yl group, pyrrolidine-3-yl group, piperidinone-1-yl group, pyrrolidinone-1-yl group, piperazine-1-yl group, morpholine-4-yl group, or a cyclic alkyl group having 3 to 8 carbon atoms such as cyclohexyl group or cyclopentyl group.
The heteroaryl group, pyrrolidine-3-yl group, piperazine-1-yl group, piperidine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, cyclopentyl group, morpholine-4-yl group and cyclic alkyl groups having 3 to 8 carbon atoms may be unsubstituted or substituted. When they have two or more substituents, these substituents may form a ring together. The substituents are those described above with reference to F in above general formula (1). The rings formed by these substituents are, for example, those described above with reference to group A, and tetrahydroisoquinoline
Furthermore, the meaning of F in the formula (1-1) is the same as that of F in the formula (1).
Preferred substituents in general formulae (1) and (1-1) in the present invention are as described below.
A is preferably a group of general formula (2), 1-naphthyl group, 2-naphthyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group.
B is preferably a group of general formula (3) [particularly preferably a group of general formula (3) wherein R6 represents hydrogen atom, an aryl-lower alkenyl group, a heteroaryl-lower alkenyl group or a cyano-lower alkyl group], a group of general formula (4) [particularly preferably a group of general formula (4) wherein either R7 or R8represents hydrogen atom], or a group, which is condensed with C to form a lactone ring, such as cyano group, nitro group, acetyl group, tetrazole group or triazole group.
C is preferably hydrogen atom, a lower alkyl group, cyano group, chloromethyl group, hydroxymethyl group, hydroxyethoxymethyl group or aminoethoxymethyl group.
D is preferably hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or aryl-lower alkyl group.
E is preferably hydrogen atom, a lower alkyl group, cyano group, chloromethyl group, hydroxymethyl group, hydroxyethoxymethyl group or aminoethoxymethyl group. X1 is preferably an interatomic bond, xe2x80x94CHxe2x95x90CHxe2x80x94or xe2x80x94Cxe2x89xa1Cxe2x80x94, and F is preferably a group of general formula (15), thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, imidazole-1-yl group, another heteroaryl group, piperidine-1-yl group, piperidine-4-yl group, pyrrolidine-1-yl group, pyrrolidine-3-yl group or morpholine-4-yl group. G is preferably hydrogen atom or a lower alkyl group.
Y is preferably a group of any of general formulae (5) to (7), (8)-1 and (9)-(14). R0 is preferably hydrogen atom. Among these groups, preferred groups are those represented by general formula (6) wherein R9 and R10 are particularly preferably hydrogen atom, and those represented by general formulae (7), (8)-1, (8)-2 or (8)-3 wherein R0 is particularly preferably hydrogen atom.
J is preferably a group represented by general formula (J-1) wherein G, Y and F are preferably those described above for general formula (1).
I is preferably an aryl-lower alkyl group, a heteroaryl-lower alkyl group, an aryl group or a heteroaryl group.
In the present invention, Y in general formula (1) is preferably a group represented by general formula (6).
Preferably in general formula (1), D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (6) wherein R9 and R10 are each hydrogen atom.
Preferably in general formula (1), B is a group of general formula (3), a group of general formula (4) wherein either R7 or R8 represents hydrogen atom, or a group which is condensed with C to form a lactone ring, D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (6) wherein R9 and R10 are each hydrogen atom.
Preferably in general formula (1), B is a group of general formula (3) wherein R6 represents hydrogen atom, D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (6) wherein R9 and R10 are each hydrogen atom.
Preferably in general formula (1), B is a group of general formula (3) wherein R6 represents hydrogen atom, or a group of general formula (4) wherein R7 or R8 each represents hydrogen atom, D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (7), (8)-1, (8)-2 or (8)-3 wherein R0 is particularly preferably hydrogen atom. More preferably, B is a group of general formula (3) wherein R6 represents hydrogen atom.
Preferably in general formula (1), B is a group of general formula (3) wherein R6 represents a group other than hydrogen atom, D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (7), (8)-1, (8)-2 or (8)-3 wherein R0 is particularly preferably hydrogen atom.
Preferably in general formula (1), B is a group of general formula (3) wherein R6 represents an aryl-lower alkenyl group, a heteroaryl-lower alkenyl group or a cyano-lower alkyl group, D is hydrogen atom, G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (7), (8)-1, (8)-2 or (8)-3 wherein R0 is particularly preferably hydrogen atom.
Preferably in general formula (1), A is a group of general formula (2), B is a group of general formula (3) wherein R6 represents hydrogen, D is hydrogen atom, F is a group of general formula (15), G is hydrogen atom, X1 is an interatomic bond, and Y is a group of general formula (6) wherein R9 and R10 are each hydrogen atom.
Preferably in general formula (1-1), A is a group of general formula (2), B is a group of general formula (3) wherein R6 represents hydrogen, D is hydrogen atom, and J is a group of general formula (J-2) wherein m represents 2 and I represents benzyl group or a group of general formula (J-3) wherein n represents 2, and I represents phenyl group.
Among the compounds of general formula (1), those of following general formula (1-a) are preferred: 
wherein
R1, R2, R3, R4 and R5 are as defined above,
B represents a group of above general formula (3) or (4) wherein R6 to R8 are as defined above,
C and E each represent a lower alkyl group,
R13 to R17 are as defined above, and
Y is represented by above general formula (6) or (7) wherein R0 is preferably hydrogen atom, and R9 and R10 are each hydrogen atom.
In the present invention, preferred dihydropyridine derivatives are those of general formula (1-a) or pharmaceutically acceptable salts thereof, wherein B is represented by above general formula (3) wherein R6 represents hydrogen atom, C and E are each methyl group, and Y is represented by above general formula (6) wherein R9 and R10 each represent hydrogen atom.
The dihydropyridine derivatives (1) of the present invention can be produced by processes described below.
For example, dihydropyridine derivatives (1-2) wherein B is carboxyl group general formula (3) wherein R6 represents hydrogen atom, C and E are each methyl group and D is hydrogen atom can be produced as follows: 
Namely, a compound (26) obtained by Knoevenagel reaction of an aldehyde (24) and an acetoacetamide (25) is reacted with 2-cyanoethyl 3-aminocrotonate (27) to obtain a compound (28), which is then treated with a base such as sodium hydroxide to obtain a dihydropyridine derivative (1-2) of the present invention. Further, the compound (28) can be obtained also by directly reacting the aldehyde (24) with the acetoacetamide (25) and 2-cyanoethyl 3-aminocrotonate (27).
Further, dihydropyridine derivatives (1-2) can be obtained as follows: 
Namely, a compound (30) is obtained by Knoevenagel reaction of an aldehyde (24) and benzyl acetoacetate (29). This compound is reacted with 2-cyanoethyl 3-aminocrotonate (27) to obtain a dihydropyridine derivative (31), which is then converted into a compound (32) by, for example, the catalytic reduction. The compound (32) is condensed with an amine (33) to obtain an amide derivative (34), which is treated with a base such as sodium hydroxide to obtain a dihydropyridine derivative (1-2) of the present invention. Further, dihydropyridine derivatives (1-3), wherein B is an ester group of general formula (3) wherein R6 is a substituent other than hydrogen atom, C and E are each methyl group, and D is hydrogen atom, can be produced as follows: 
Namely, the dihydropyridine derivative (1-2) synthesized by the above-described method is reacted with an alcohol (35) to obtain a dihydropyridine derivative (1-3) of the present invention.
Dihydropyridine derivatives (1-4) of the above formula wherein B is a substituted carbamoyl group of general formula (4), C and E each represent methyl group, and D is hydrogen atom can be obtained as follows: 
Namely, the dihydropyridine derivative (1-2) synthesized by the above-described method is condensed with a substituted amine (36) to obtain a dihydropyridine derivative (1-4) of the present invention.
Dihydropyridine derivatives (1-5) of the above formula wherein B is a cyano group, C and E each represent methyl group, and D is hydrogen atom can be obtained as follows: 
Namely, a dihydropyridine derivative (1-5) of the present invention can be produced by reacting a compound (26) [obtained by Knoevenagel reaction of an aldehyde (24) and an acetoacetamide (25)] with 3-aminocrotonitrile (37).
When the acetoacetamides (25) used as the starting material are not well-known, they can be produced by, for example, the following method: 
For example, the acetoacetamides (25) can be obtained by heating an amine (33) and a diketene (38) with a suitable base.
Dihydropyridine derivatives (1-6) wherein B is carboxyl group [general formula (3) wherein R6 is hydrogen atom], C is methyl group and D is hydrogen atom can be produced as follows: 
Namely, Meldrum""s acid (39) is reacted with an acyl chloride (40) in the presence of a suitable base to obtain a compound (41), which is then reacted with benzyl alcohol (42) to obtain a benzyl acylacetate (43). This ester (43) is then subjected to Knoevenagel reaction with an aldehyde (24) to obtain a compound (44), which is reacted with 2-cyanoethyl 3-aminocrotonate (27) to obtain a dihydropyridine derivative (45). This compound is converted into a compound (46) by, for example, the catalytic reduction. The compound (46) is condensed with an amine (33) to obtain an amide derivative (47), which is treated with a base such as sodium hydroxide to obtain a dihydropyridine derivative (1-6) of the present invention.
The benzyl acylacetate (43) used in the above-described process can be obtained also by transesterifying a methyl acylacetate (48) with benzyl alcohol (42). 
When the compounds of general formula (1) of the present invention can form salts, the salts must be pharmaceutically acceptable ones. The salts are ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, salts with organic amines such as morpholine and piperidine, and salts with basic amino acids such as arginine and lysine.
The compounds of general formula (1) or salts thereof can be administered as they are or in the form of various medicinal compositions. The forms of the medicinal compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets and depots. They can be prepared with an ordinary preparation assistants.
For example, tablets can be prepared by mixing the dihydropyridine derivative used as the active ingredient of the present invention with a known assistant material such as an inert diluent, e. g. lactose, calcium carbonate or calcium phosphate; a binder, e. g. acacia, corn starch or gelatin; an excipient, e. g. alginic acid, corn starch or pregelatinized starch; a sweetening agent, e. g. sucrose, lactose or saccharin; a flavoring agent, e. g. peppermint, cherry; and magnesium stearate, talc or carboxymethylcellulose.
The N-type calcium channel antagonists containing one of the compounds of general formula (1) and salts thereof are usable as therapeutic agents for any of encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e. g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; various pains, e. g. neuropathy caused by head injury; sharp pain caused by spinal injury, diabetes or thromboangitis obliterans; pain after an operation; migraine and visceral pain; various diseases caused by psychogenic stress, e. g. bronchial asthma; unstable angina and hypersensitive colon inflammation; emotional disorder; and drug addiction withdrawal symptoms, e. g. ethanol addiction withdrawal symptoms.
The dosage of the therapeutic agent used for the above-described purpose varies depending on the intended therapeutic effect, method of administration, period of therapy, age, body weight, etc. Usually, it is given to adults in an amount of 1 xcexcg to 5 g/day in the oral administration, and 0.01 xcexcg to 1 g/day in the parenteral administration.